[Federal Register Volume 62, Number 92 (Tuesday, May 13, 1997)]
[Rules and Regulations]
[Pages 26225-26228]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12461]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. 87G-0351]


Food Additives Permitted for Direct Addition to Food for Human 
Consumption; 1,3-Butylene Glycol

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the food 
additive regulations to provide for the safe use of 1,3-butylene glycol 
as a formulation and processing aid in the manufacture of edible 
sausage casings. This action is in response to a petition filed by 
Teepak, Inc.

DATES: Effective May 13, 1997; written objections and requests for a 
hearing by June 12, 1997. The Director of the Office of the Federal 
Register approves the incorporation by reference in accordance with 5 
U.S.C. 552(a) and 1 CFR part 51 of a certain publication listed in new 
Sec. 172.712, effective May 13, 1997.

ADDRESSES: Submit written objections to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: James C. Wallwork, Center for Food 
Safety and Applied Nutrition (HFS-215), Food and Drug Administration, 
200 C St. SW., Washington, DC 20204-0001, 202-418-3078.

SUPPLEMENTARY INFORMATION:

I. Background

    In accordance with the procedures described in Sec. 170.35 (21 CFR 
170.35), Teepak, Inc., 915 North Michigan Ave., Danville, IL 61832-
0597, submitted a petition (GRASP 7G0332) requesting that 1,3-butylene 
glycol be affirmed as generally recognized as safe (GRAS) for use in 
food as a formulation and processing aid, when used in accordance with 
current good manufacturing practice.
    FDA published a notice of filing of this petition in the Federal 
Register of November 23, 1987 (52 FR 44936), and gave interested 
parties an opportunity to submit comments concerning the petition to 
the Dockets Management Branch (address above). FDA received no comments 
in response to that notice.
    After the petition was filed, the petitioner amended the petition 
to limit the scope of the requested GRAS affirmation. As amended, the 
petition asks FDA to affirm 1,3-butylene glycol as GRAS for use only as 
a formulation and processing aid in the manufacture of edible sausage 
casings.

II. Standard for Evaluation of Petition

    Under Sec. 170.30 (21 CFR 170.30), general recognition of safety 
may be based only on the views of experts qualified by scientific 
training and experience to evaluate the safety of substances added to 
food. The basis of such views may be either: (1) Scientific procedures, 
or (2) in the case of a substance used in food prior to January 1, 
1958, experience based on common use in food (Sec. 170.30(a)). General 
recognition of safety based upon scientific procedures requires the 
same quantity and quality of scientific evidence as is required to 
obtain approval of the substance as a food additive and ordinarily is 
to be based upon published studies, which may be corroborated by 
unpublished studies and other data and information (Sec. 170.30(b)). In 
its petition, Teepak, Inc., has not claimed a history of common use in 
food before 1958, but rather has relied upon scientific procedures, 
primarily published scientific papers, to support its claim that 1,3-
butylene glycol is GRAS.
    In reviewing the data in the petition and other relevant material, 
FDA noted that the published studies on the safety of 1,3-butylene 
glycol are of varying quality. As discussed in section IV. of this 
document, the agency believes that the available data, taken together, 
establish the safety of 1,3-butylene glycol for the limited use 
requested in the petition. However, FDA does not believe that the data 
are sufficient to show that the basis for such a safety determination 
is generally recognized by experts in the field.
    Thus, in accordance with 21 CFR 170.35(c)(5) and 170.38, the agency 
has determined that the requested use of 1,3-butylene glycol cannot be 
considered GRAS based upon scientific procedures and that the compound 
is a food additive subject to section 409 of the Federal Food, Drug, 
and Cosmetic Act (the act) (21 U.S.C. 348). FDA notified the petitioner 
of this conclusion and the firm agreed that 1,3-butylene glycol could 
be evaluated as a food additive rather than as a GRAS ingredient.

III. Introduction

A. Identity

    1,3-Butylene glycol 
(CH2OHCH2CHOHCH3, CAS Reg. No.

[[Page 26226]]

107-88-0, and molecular weight 90.12) is the common name for 1,3-
dihydroxybutane or 1,3-butanediol. It is a clear, colorless, 
hygroscopic, viscous liquid almost without odor.

B. Regulated Food and Packaging Uses

    1,3-Butylene glycol is regulated for use under 21 CFR 173.220 1,3-
Butylene glycol as a solvent for natural and synthetic flavoring 
substances, except where food standards preclude its use. Also, 1,3-
butylene glycol is regulated for use in polyester formation under 21 
CFR 175.320 Resinous and polymeric coatings for polyolefin films and as 
a reactant under 21 CFR 177.1680 Polyurethane resins in the preparation 
of resins for use in contact with dry bulk foods.

IV. Safety

A. Manufacturing Process

    1,3-Butylene glycol is produced through the controlled aldol 
condensation of acetaldehyde in the presence of dilute aqueous sodium 
hydroxide. The first reaction product, a trimer of acetaldehyde, is 
decomposed to a dimer, acetaldol (3-hydroxy-butyraldehyde), during the 
neutralization of the excess sodium hydroxide with dilute acetic acid. 
The unreacted acetaldehyde is removed by distillation. Acetaldol is 
then reduced to butylene glycol by hydrogenation in the presence of a 
nickel catalyst. 1,3-Butylene glycol thus produced is purified in a 
series of vacuum distillation towers. The product is manufactured to 
conform to the identity and specifications listed in the monograph 
entitled ``1,3-Butylene Glycol'' in the Food Chemicals Codex, 4th ed. 
(1996), p. 52.

B. Proposed Use in Food

    The petition contains data demonstrating that 1,3-butylene glycol 
is effective in reducing breakage in manufactured sausage casings. The 
petition also contains data demonstrating that the petitioned substance 
is most effective at levels of 5 to 15 percent of the liquid phase of 
the casing (equivalent to 2 to 6 percent of the total casing weight). 
Included in the petition are data demonstrating that at levels higher 
than 6 percent, 1,3-butylene glycol sausage casings become more 
susceptible to breakage. Thus, the petition provides data demonstrating 
that the proposed ingredient is technologically self-limiting.

C. Consumer Exposure

    Using sausage intake data from the Market Research Corp. of America 
(Ref. 1) and assuming from information submitted with the petition that 
1 percent of the weight of sausage is casing made with 6 percent 1,3-
butylene glycol, FDA estimates that exposure to the proposed ingredient 
is 6.0 milligrams/person/day (mg/p/d) (mean) and 12 mg/p/d (90th 
percentile) for the 2+ years age group. For the 2- to 5-year-old age 
group subcategory, FDA estimates that exposure is 4.5 mg/p/d (mean) and 
8.5 mg/p/d (90th percentile).

D. Toxicology

    To provide evidence of the safety of 1,3-butylene glycol for the 
petitioned use, the petitioner provided published and unpublished 
reproduction and chronic feeding studies in rats and dogs, as well as a 
number of published short-term nutrition and metabolism studies. In 
addition, an agency-initiated literature search identified a 
reproduction study with 1,3-butylene glycol published in 1990.
    A published 2-year dietary feeding study (Ref. 2) in beagle dogs 
reported no visible adverse effects on appearance, behavior, growth, 
food intake, urinalysis, hematology or serum biochemistry that could be 
attributed to treatment with 1,3-butylene glycol. The diets of male and 
female dogs were treated with the petitioned substance at 118, 228, and 
613 mg/kilogram body weight/day (mg/kg bw/d) for males and 101, 228, 
and 732 mg/kg bw/d for females. Although microscopic lesions were 
observed in testes and lymph nodes of males after 1 and 2 years' 
treatment, FDA concludes that the lesions do not appear to be of 
pathological significance. Lesions of the type and severity observed 
are frequent incidental findings in dogs. Moreover, no significant 
difference in appearance between lesions in control and treated animals 
could be derived from the histopathological descriptions of the tissues 
examined. Therefore, the agency finds that the incidence of gross 
pathological lesions is unrelated to treatment and that this study 
supports a no-effect level of 700 mg/kg bw/d, the highest dose in the 
study.
    The agency concludes that data from a published 2-year dietary 
feeding study (Ref. 2) in Sprague-Dawley rats cannot be used to 
establish the safety of 1,3-butylene glycol. The study had insufficient 
statistical power to detect an adverse response to 1,3-butylene glycol 
because an inadequate number of rats was used and widespread disease 
killed most of the rats during the second year of the study.
    A published reproduction study (Ref. 3) in Long-Evans rats, treated 
by gavage with 1,3-butylene glycol (0, 706, 4,236, and 7,060 mg/kg bw/
d) during days 6 to 15 of gestation, also reported no treatment-related 
effects on a variety of reproduction parameters (litter weight and 
size, crown-rump length, corpora lutea, implantation sites, sex 
distribution, intrauterine deaths, total malformed pups or incidence of 
litters with malformed pups). However, the researchers reported an 
increased incidence of low body weights and sternebral anomalies in 
pups from high-dose mothers, indicating a possible teratogenic effect 
from exposure to 1,3-butylene glycol. The full significance of the 
effects of the treatment of rats with 1,3-butylene glycol, though, 
cannot be determined from the available data. FDA finds that the data 
are insufficient to determine whether the observed anomalies were 
caused by the treatment-related reductions in birth weight or by a 
teratogenic effect of the additive. However, because the observed low 
body weights and sternebral anomalies occurred only in high-dose 
groups, the agency concludes that a no-effect level can be set from 
doses employed with mid-dose rats at 4,200 mg/kg bw/d.
    A number of published and unpublished nutritional and metabolic 
studies with 1,3-butylene glycol were also provided (Refs. 4 through 
21). Within the limited scope of those studies no significant 
toxicological effects were reported except in a human clinical study 
(Ref. 21). In that study, 1,3-butylene glycol fed to young male and 
female subjects (250 mg/kg bw/d in bread for four separate 7-day 
periods) was reported to significantly depress blood glucose (lowered 
by 12 percent relative to controls). The 1,3-butylene glycol-induced 
glucose reduction did not involve insulin or growth hormone, although 
its mechanism could not be determined. As discussed in section IV.D.1. 
of this section, the reduction in blood glucose would not be expected 
to occur at the low levels estimated for human dietary exposure from 
the proposed use of 1,3-butylene glycol.
    Ordinarily, chronic studies in rodent and nonrodent species are 
needed to establish the safety of direct food ingredients (Ref. 22). 
Although the petitioner did not submit an acceptable chronic dietary 
rodent study, FDA concludes that the toxicological data submitted are 
adequate to establish the safety of the use of 1,3-butylene glycol in 
edible sausage casings, for the following reasons:
    1. The metabolism of 1,3-butylene glycol is well understood. In the 
rat, 1,3-butylene glycol is metabolized in the liver cytosol in a 
manner similar to ethanol (Refs. 13 and 16). In the intact rat and in 
tissue slices, it is converted

[[Page 26227]]

to acetoacetate and -hydroxybutyrate, which are normal 
intermediates in fat metabolism. In the kidney, 1,3-butylene glycol 
blocks gluconeogenesis at the conversion of 3-phosphoglycerate to 
glyceraldehyde-3-phosphate (Ref. 14). This metabolic blockage is 
responsible for the reduction in serum glucose that occurs when 1,3-
butylene glycol is consumed at sufficiently high levels. At consumption 
levels that would be expected from the proposed use, however, 1,3-
butylene glycol would not be expected to inhibit gluconeogenesis in the 
kidney. In addition, from an examination of the scientific literature 
on the metabolism of 1,3-butylene glycol, which is well understood and 
documented (Refs. 16 and 21), there is no indication that 1,3-butylene 
glycol would be expected to have any carcinogenic potential. Therefore, 
FDA concludes that a chronic rodent study is not necessary to support 
the safety of the proposed use of 1,3-butylene glycol.
    2. To ensure an adequate margin of safety, FDA applied a 1,000-fold 
safety factor (rather than the normal 100-fold safety factor) to the 
no-effect level from the dog study (Ref. 2) to compensate for the lack 
of an acceptable chronic rodent study for 1,3-butylene glycol. Applying 
a 1,000-fold safety factor to the no-effect level from the dog study 
gives an acceptable daily intake (ADI) for 1,3-butylene glycol of 0.7 
mg/kg bw. Although an adverse metabolic effect (decreased serum 
glucose) was reported in humans consuming 250 mg 1,3-butylene glycol/kg 
bw, it is unlikely that any such metabolic effects would be observed at 
the ADI, which is 350-fold lower. Furthermore, for 1,3-butylene glycol, 
the ADI (0.7 mg/kg bw) is greater than the daily exposure estimates of 
0.1 mg/kg bw (mean) and 0.2 mg/kg bw (90th percentile) for adults, 
assuming a bw of 60 kg, and 0.3 mg/kg bw (mean) and 0.6 mg/kg bw (90th 
percentile) for 2- to 5-year-olds, assuming a body weight of 15 kg. 
Therefore, the agency concludes that the level of exposure resulting 
from the petitioned use of 1,3-butylene glycol is safe.

V. Conclusion on Safety

    FDA has evaluated the data in the petition and other relevant 
material regarding the use of 1,3-butylene glycol as a formulation and 
processing aid in sausage casings and concludes that the substance 
produces the intended technical effects and is safe under the proposed 
conditions of use. Therefore, the agency is amending the food additive 
regulations to provide for the requested use.
    In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition 
and the documents that FDA considered and relied upon in reaching its 
decision to approve the petition are available for inspection at the 
Center for Food Safety and Applied Nutrition by appointment with the 
information contact person listed above. As provided in Sec. 171.1(h), 
the agency will delete from the documents any materials that are not 
available for public disclosure before making the documents available 
for inspection.

VI. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this action. FDA has concluded that the action will not have 
a significant impact on the human environment, and that an 
environmental impact statement is not required. The agency's finding of 
no significant impact and the evidence supporting that finding, 
contained in an environmental assessment, may be seen in the Dockets 
Management Branch (address above) between 9 a.m. and 4 p.m., Monday 
through Friday.

VII. Objections

    Any person who will be adversely affected by this regulation may at 
any time on or before June 12, 1997, file with the Dockets Management 
Branch (address above) written objections thereto. Each objection shall 
be separately numbered, and each numbered objection shall specify with 
particularity the provisions of the regulation to which objection is 
made and the grounds for the objection. Each numbered objection on 
which a hearing is requested shall specifically so state. Failure to 
request a hearing for any particular objection shall constitute a 
waiver of the right to a hearing on that objection. Each numbered 
objection for which a hearing is requested shall include a detailed 
description and analysis of the specific factual information intended 
to be presented in support of the objection in the event that a hearing 
is held. Failure to include such a description and analysis for any 
particular objection shall constitute a waiver of the right to a 
hearing on the objection. Three copies of all documents shall be 
submitted and shall be identified with the docket number found in 
brackets in the heading of this document. Any objections received in 
response to the regulation may be seen in the Dockets Management Branch 
between 9 a.m. and 4 p.m., Monday through Friday.

VIII. References

    The following references have been placed on display in the Dockets 
Management Branch (address above ) and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Memorandum from M. DiNovi, Chemistry Review Branch, to R. L. 
Martin, Direct Additives Branch, dated November 8, 1988.
    2. Scala, R. A., and O. E. Paynter, ``Chronic Oral Toxicity of 
1,3-Butanediol,'' Toxicology and Applied Pharmacology, 10:160-164, 
1967.
    3. Mankes, R. F., V. Renak, J. Fieseher, and R. LeFevre, 
``Birthweight Depression in Male Rats Contiguous to Male Siblings in 
Utero Exposed to High Doses of 1,3-Butanediol During 
Organogenesis,'' Journal of the American College of Toxicology, 
5:189-196, 1986.
    4. Dymsza, H. A., ``Nutritional Application and Implication of 
1,3-Butanediol,'' Federation Proceedings, 34:2167-2170, 1975.
    5. Giron, H. M., ``Some Aspects of the Utilization of 1,3-Diols 
as Synthetic Dietary Energy Sources'' (thesis for master of science 
degree), Massachusetts Institute of Technology, August 1968.
    6. Food and Drug Research Laboratories, Inc., Morgareidge, K., 
``Utilization of 1,3-Butylene Glycol in Dogs,'' November 1, 1972.
    7. Mehlman, M. A., ``Synthetic Food Additives as a Source of 
Calories: 1,3-Butanediol,'' Federation Proceedings, 34:2166, 1975.
    8. Miller, S. A., and H. A. Dymsza, ``Utilization by the Rat of 
1,3-Butanediol as a Synthetic Source of Dietary Energy,'' Journal of 
Nutrition, 91:79-88, 1967.
    9. Stoewsand, G. S., H. A. Dymsza, M. A. Kilmore, and S. M. 
Swift, ``Plasma Lipid Changes in Exercised Dogs Fed 1,3-
Butanediol,'' Federation Proceedings, 25:608, 1966 (abstract).
    10. Young, J. W., ``Use of 1,3-Butanediol for Lactation and 
Growth in Cattle,'' Federation Proceedings, 34:2177-2181, 1975.
    11. Mackerer, C. R., R. N. Saunders, J. R. Haettinger, and M. A. 
Mehlman, ``Influence of 1,3-Butanediol on Blood Glucose 
Concentration and Pancreatic Insulin Content of Streptozotocin-
Diabetic Rats,'' Federation Proceedings, 34:2191-2196, 1975.
    12. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Metabolic 
Control of Enzymes in Normal, Diabetic and Diabetic Insulin Treated 
Rats Utilizing 1,3-Butanediol'' (undated).
    13. Mehlman, M. A., R. B. Tobin, H. K. J. Hahn, V. DeVore, and 
L. Kleager, ``Metabolic Fate of 1,3-Butanediol (BD) in the Rat,'' 
Omaha, NE (undated).
    14. Mehlman, M. A., R. B. Tobin, and J. B. Johnston, ``Influence 
of Dietary 1,3-Butanediol on Metabolites and Enzymes Involved in 
Gluconeogenesis and Lipogenesis in Rats,'' Journal of Nutrition, 
100:1341-1346, 1970.
    15. Mehlman, M. A., R. B. Tobin, and C. R. Mackerer, ``1,3-
Butanediol Catabolism in the Rat,'' Federation Proceedings, 34:2182-
2185, 1975.
    16. Nahapetian, A., ``Metabolism in Vivo of 1,3-Butanediol in 
the Rat'' (thesis for doctor of science degree), Massachusetts 
Institute of Technology, September 1971.
    17. Parker, M. M. (under the supervision of Myron A. Mehlman), 
``Metabolic Effects of 1,3-Butanediol,'' Omaha, NE, August 1972.

[[Page 26228]]

    18. Romsos, D. R., P. S. Belo, and G. A. Leveille, ``Butanediol 
and Lipid Metabolism,'' Federation Proceedings, 34:2186-2190, 1975.
    19. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``The 
Metabolism of 1,3-Butanediol'' (undated).
    20. Tate, R. L., M. A. Mehlman, and R. B. Tobin, ``Metabolic 
Fate of 1,3-Butanediol in the Rat: Conversion to -
Hydroxybutyrate,'' Journal of Nutrition, 101:1719-1726, 1971.
    21. Tobin, R. B., M. A. Mehlman, C. Kies, H. M. Fox, and J. S. 
Soeldner, ``Nutritional and Metabolic Studies in Humans With 1,3-
Butanediol,'' Federation Proceedings, 34:2171-2176, 1975.
    22. ``Toxicological Principles for the Safety Assessment of 
Direct Food Additives and Color Additives Used in Food'' in 
``Redbook,'' Center for Food Safety and Applied Nutrition, Food and 
Drug Administration, 1982. Available through National Technical 
Information Service (NTIS), 5285 Port Royal Rd., Springfield, VA 
22161, order number PB-83-170696. Revised draft is available from 
the Office of Premarket Approval (HFS-206), 200 C St. SW., 
Washington, DC 20204-0001.

List of Subjects in 21 CFR Part 172

    Food additives, Incorporation by reference, Reporting and 
recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs and 
redelegated to the Director, Center for Food Safety and Applied 
Nutrition, 21 CFR part 172 is amended as follows:

PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR 
HUMAN CONSUMPTION

    1. The authority citation for 21 CFR part 172 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 409, 701, 721 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 348, 371, 
379e).

    2. New Sec. 172.712 is added to subpart H to read as follows:

Sec. 172.712  1,3-Butylene glycol.

    The food additive 1,3-butylene glycol (CAS Reg. No. 107-88-0) may 
be safely used in food in accordance with the following prescribed 
conditions:
    (a) It is prepared by the aldol condensation of acetaldehyde 
followed by catalytic hydrogenation.
    (b) The food additive shall conform to the identity and 
specifications listed in the monograph entitled ``1,3-Butylene Glycol'' 
in the Food Chemicals Codex, 4th ed. (1996), p. 52, which is 
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR 
part 51. Copies are available from the Office of Premarket Approval, 
Center for Food Safety and Applied Nutrition, 200 C St. SW., 
Washington, DC 20204-0001, or may be examined at the Center for Food 
Safety and Applied Nutrition's Library, Food and Drug Administration, 
200 C St. SW., rm. 3321, Washington, DC, or at the Office of the 
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.
    (c) It is used in the manufacture of sausage casings as a 
formulation aid as defined in Sec. 170.3(o)(14) of this chapter and as 
a processing aid as defined in Sec. 170.3(o)(24) of this chapter.

    Dated: April 14, 1997.
Fred R. Shank,
Director, Center for Food Safety and Applied Nutrition.
[FR Doc. 97-12461 Filed 5-12-97; 8:45 am]
BILLING CODE 4160-01-F